Process for preparing intermediates for the synthesis of D1 antagonists

ABSTRACT

Disclosed are a process and intermediates of the formula ##STR1## wherein R is --CH 3  or --C(O)--OR 1 , and R 1  is C 1  -C 6  alkyl or --CH 2  C 6  H 5  ; or the formula ##STR2## wherein: R 2  is H or OH, R is --C(O)OR 1  and R 1  is C 1  -C 6  alkyl or --CH 2  C 6  H 5 , or where R 2  is H, R can also be CH 3  ; for preparing benzazepine intermediates of the formula ##STR3## The benzazepine intermediates are useful for preparing benzazepines having activity as selective D1 receptor antagonists.

This is a division, of application Ser. No. 08/127,667, filed Sep. 27,1993 U.S. Pat. No. 5,461,147.

BACKGROUND OF THE INVENTION

The present invention relates to a process for preparing intermediatesuseful in the preparation of benzazepines having activity as selectiveD1 receptor antagonists.

U.S. Pat. No. 4,973,586 discloses fused benzazepines, and in particularthe compound known as SCH 39166, having the structure ##STR4## asselective D1 antagonists useful in the treatment of psychoses,depression, pain and D1 dependent neurological disorders. Methods forpreparing such compounds are also described therein.

Berger, et al, J. Med. Chem., 32, 1913-1921 (1989), discloses a processfor preparing SCH 39166 comprising acid promoted cyclization of acompound of the formula (1) to give a 1:1 mixture of cis and transbenzazepines (cis-2 and trans-2, respectively). Compound trans-2 is thenconverted to racemic compound I via a multi-step procedure. Compound Iis resolved via its di-O,O'-p-tolyltartrate salt and hydrolyzed with HBrand HOAc to give SCH 39166. ##STR5##

The prior art process suffers from several shortcomings. It isinefficient, producing a 1:1 mixture of cis and trans benzazepines inthe cyclization step. In addition, conducting the resolution step at alate stage of the synthesis is very costly and adds furtherinefficiency. Therefore, it was desirable to develop a chemicallyefficient and cost effective process for preparing SCH 39166 of highoptical purity. It was also desired that the resolution be performed atan early stage of the process or that the chiral centers be introducedusing inexpensive chiral starting materials, thereby avoiding the needfor resolution.

SUMMARY OF THE INVENTION

The present invention comprises a process for preparing compounds of theformula I ##STR6## comprising the steps: (a) cyclizing an alcohol of theformula ##STR7## wherein R is --CH₃ or--C(O)--OR¹, and R¹ is C₁ -C₆alkyl or --CH₂ C₆ H₅ ; and, where R is --C(O)--OR¹, reducing thecyclyzed product with a hydride reducing agent; to form an amine of theformula ##STR8## (b) reacting the amine of Step (a) with a compound ofthe formula J--CH₂ --Q, wherein J is a leaving group and Q is a group ofthe formula ##STR9## wherein R² is C₁ -C₆ alkyl, to form a compound ofthe formula ##STR10## (c) cyclizing the product of step (b) and treatingthe cyclized product with a hydride reducing agent to give a compound offormula I.

The present invention further comprises a process, designated Process A,for preparing compounds of the formula I, wherein the alcohol of step(a) is prepared by a process comprising the steps:

(A1) treating L-homophenylalanine with an C₁ -C₆ alkyl or benzylchloroformate in the presence of a strong base to form a carbamate ofthe formula ##STR11## wherein R¹ is as defined above;

(A2) treating the carbamate of step (A 1) with paraformaldehyde in thepresence of an acid catalyst to form an oxazolidinone of the formula##STR12## wherein R¹ is as defined above; (A3) treating theoxazolidinone of step (A2) with a reagent of the formula ##STR13##wherein M is selected from MgL, ZnL, TiL₃, CeL₂, MnL or CuL, and L is ahalide selected from Br, Cl or I, to form a 5-hydroxy-oxazolidine of theformula ##STR14##

(A4) converting the 5-hydroxyoxazolidine of step (A3) to an alcohol ofStep (a) by:

(i) treating the 5-hydroxyoxazolidine with an acid selected fromBF₃,.OEt₂, HCl, pTSA and HClO₄ to form a ketone of the formula ##STR15##wherein R¹ is as defined above and treating the ketone of step (A4) witha hydride reducing agent; or

(ii) treating the 5-hydroxyoxazolidine with a hydride reducing agent; toform the alcohol of Step (a).

In an alternative embodiment, the present invention further comprises aprocess, designated Process B, for preparing compounds of the formula Iwherein the alcohol of step (a) is prepared by a process comprising thesteps:

(B1) treating the carbamate of step (A1) of Process A:

(i) with CH₃ O--N(H)CH₃ or CH₃ O--N(H)CH₃.HCl in the presence of BOP anda tertiary amine base; or

(ii) with SOCl₂ or (COCl)₂ to form an acid chloride and treating theacid chloride with CH₃ O--N(H)CH₃ or CH₃ O--N(H)CH₃.HCl and pyridine;

to give a compound of the formula ##STR16## wherein R¹ is as definedabove; (B2) treating the product of step (B1) with a reagent of theformula ##STR17## wherein M is selected from MgL, ZnL, TiL₃, CeL₂, MnLor CuL, and L is a halide selected from Br, Cl or I, to form a ketone ofthe formula ##STR18## wherein R¹ is as defined above; (B3) treating theketone of step (B2) with a hydride reducing agent to form the alcohol ofStep (a).

In a second alternative embodiment, the present invention comprises aprocess, designated Process C, for preparing a compound of the formula Icomprising the steps:

(C₁) reacting a ketocarbamate of the formula ##STR19## wherein R¹ is asdefined above, with the lithium reagent prepared from5-bromo-2-chloroanisole and t-butyllithium, to form a compound of theformula ##STR20## wherein R¹ is as defined above; (C2) reacting theproduct of step (C1) with a trialkylsilane and CF₃ CO₂ H to form acompound of the formula ##STR21## wherein R¹ is as defined above, as amixture of cis and trans isomers;

(C3) reducing the product of step (C2) by treating with a hydridereducing agent to form a compound of the formula ##STR22## as a mixtureof cis and trans isomers; (C4) reacting the product of Step (C3) with acompound of the formula J--CH₂ --Q, wherein J is a leaving group and Qis a group of the formula ##STR23## wherein R² is C₁ -C₆ alkyl, to forma compound of the formula ##STR24## as a mixture of cis and transisomers; (C5) treating the product of step (C4) with an alkoxide base toform a compound of the formula ##STR25## (C6) cyclizing the product ofstep (C5) to form the compound of formula I.

Preferred is a process of the present invention wherein: the cyclizationof Step (a) comprises treating the alcohol with a strong acid,preferably CH₃ SO₃ H; the hydride reducing agent of step (a) is LiAlH₄ ;J is Br; Q is --CH(OR²)₂ and R² is CH₃ ; and the cyclization of Step (c)comprises treating with a strong acid, preferably H₂ SO₄ or CH₃ SO₃ H,followed by treatment with a hydride reducing agent, preferably TBAB orNaBH₄.

Also preferred is a process according to Process A, wherein: R¹ is CH₃-- or CH₃ CH₂ --; the alkyl chloroformate of Step (A1) is methyl orethyl chloroformate; the strong base of step (A1) is NaOH, preferably 1NNaOH; the acid catalyst of Step (A2) is p-TSA; the metal of Step (A3) isMgBr; and the hydride reducing agents of Steps (A4) (i) and (A4) (ii)are LiBH₄, LiAlH₄ or NaBH₄.

Another preferred process is the process according to Process B,wherein: R¹ is CH₃ -- or CH₃ CH₂ --; the tertiary amine base of Step(B1) is Et₃ N or pyridine; M is Li, Na or MgBr; and the hydride reducingagent of Step (B3) is LiBH₄, LiAlH₄ or NaBH₄.

Yet another preferred process is the process according to Process C,wherein: R¹ is CH₃ -- or CH₃ CH₂ --; the trialkylsilane of Step (C2) istriethylsilane; the hydride reducing agent of Step (C3) is LiAlH₄ ; J isBr; the alkoxide base of Step (C5) is KOC(CH₃)₃ or NaOC(CH₃)₃ ; and thecyclization of Step (C6) comprises treating with a strong acid,preferably H₂ SO₄ or CH₃ SO₃ H, followed by treatment with a hydridereducing agent, preferably TBAB or NaBH₄.

The process of the present invention does not suffer the shortcomings ofthe prior art process. It is chemically efficient and, by utilizinginexpensive chiral starting materials produces a chiral product(compound I) which is readily converted to SCH 39166 by known methods.

The present invention further comprises compounds of the formula##STR26## wherein R is --CH₃ or --C(O)--OR¹, and R¹ is C₁ -C₆ alkyl or--CH₂ C₆ H₅, useful as intermediates in the preparation of benzazepineshaving activity as selective D1 receptor antagonists.

In another embodiment, the present invention further comprises compoundsof the formula ##STR27## wherein R¹ is C₁ -C₆ alkyl or --CH₂ C₆ H₅,useful as intermediates in the preparation of benzazepines havingactivity as selective D1 receptor antagonists.

In yet another embodiment, the present invention further comprisescompounds of the formula ##STR28## wherein R¹ is C₁ -C₆ alkyl or --CH₂C₆ H₅, useful as intermediates in the preparation of benzazepines havingactivity as selective D1 receptor antagonists.

In still another embodiment, the present invention further comprisescompounds of the formula ##STR29## wherein: R² is H or OH, R is--C(O)OR¹, and R¹ is C₁ -C₆ alkyl or --CH₂ C₆ H₅, or where R² is H, Rcan also be CH₃, useful as intermediates in the preparation ofbenzazepines having activity as selective D1 receptor antagonists.

DETAILED DESCRIPTION

In general, stereochemical representations are meant to denote absolutestereochemistry. The process of the present invention utilizes opticallyactive starting materials and produces a single enantiomer of compoundI. The stereochemical purity of compounds is generally given in terms ofthe enantiomeric excess (e.e.).

As used herein the term "alkyl" means a straight or branched alkylchains of 1 to 6 carbon atoms;

"hydride reducing agent" means LiAlH₄, NaBH₄, NaBH₃ CN, LiBH₄ or aborane amine complex, such as borane-methylamine,borane-tert-butylamine, borane-piperidine, borane-triethylamine,borane-N,N-diisopropylethylamine, borane-N,N-diethylaniline,borane-morpholine, borane-4-ethylmorpholine or borane-4-phenylmorpholinecomplex;

"strong acid" means a protic acid having a pKa of <2, such as H₂ SO₄,CH₃ SO₃ H or CF₃ SO₃ H, which acids may optionally be used in thepresence of a Lewis Acid, such as BF₃ ;

"acid catalyst" means a suitable acid, such as p-toluenesulfonic acid;

"base" means Na₂ CO₃, K₂ CO₃, NaHCO₃ or KHCO₃ ;

"strong base" means an alkali metal hydroxide, such as NaOH, KOH orLiOH, an alkaline earth metal hydroxide such as Ca(OH)₂, or an alkalimetal hydrocarbon, such as n-butyllithium, t-butyllithium ors-butyllithium;

"alkoxide base" means an alkali metal alkoxide, such as NaOC(CH₃)₃,KOC(CH₃)₃ ;

"tertiary amine base" means a tertiary amine selected fromtriethylamine, pyridine and di-isopropylethylamine; and

"leaving group" means a halogen selected from Br, Cl or I, or asulfonate ester of the formula --OSO₂ R³, wherein R³ is methyl,trifluoromethyl or 4-methyl-phenyl.

As used herein the following reagents and solvents are identified by theabbreviations indicated: benzotriazol-1-yloxytrisdimethylamino!-phosphonium hexafluoro-phosphate (BOP);para-toluenesulfonic acid (p-TSA); tetrahydrofuran (THF); iso-propanol(i-PrOH); methanol (MeOH); ethyl acetate (EtOAc); tert-butyl methylether (t-BuOMe); triethylamine (Et₃ N); N,N-dimethylformamide (DMF);trifluoroacetic acid (TFA); dimethylsulfoxide (DMSO);borane-tert-butylamine (TBAB); boron trifluoride etherate (BF₃.OEt₂).

Where hydride reducing agents are employed the reduction products formedwill be dependent upon the specific hydride reducing agent utilized andthe reaction conditions employed. For example, the reduction of ketonescan be selectively achieved in presence of other less reactive groups,such as carbamates, by using less reactive hydride reducing agents, suchas NaBH₄, under appropriate reaction conditions.

The present invention comprises a process for preparing a compound ofthe formula I as shown in Reaction Scheme 1. ##STR30##

In Scheme 1, Step (a), the alcohol II, wherein R is CH₃, is combinedwith a strong acid, preferably CF₃ SO₃ H, in a suitable solvent, such asCH₂ Cl₂, at -40° to +20° C., preferably about 0° C., then stirred at 0°to 50° C., preferably about 25° C., for 6 to 24 hours, preferably about12 hours, to form the amine III.

Alternatively, where R is --C(O)OR¹, the alcohol II is treated with astrong acid as described above, then reduced by treating with a hydridereducing agent, preferably LiAlH₄, in a suitable solvent, such as THF,at 0° to 80° C., preferably at 65° to 70° C., to form the amine III.

In Step (b), the amine III is reacted with a compound of the formulaJ--CH₂ --Q, wherein J and Q are as defined above, preferably J is Br andQ is --CH(OCH₃)₂, in the presence of a base, preferably K₂ CO₃ or Na₂CO₃, and a suitable solvent, such as DMF, in a sealed vessel, preferablya Teflon® lined bomb, at a temperature of 60° to 150° C., preferablyabout 110° C., for 12 h to 120 h, preferably about 24 h to 36 h, to givecompound

In Step (c), compound IV is combined with a strong acid, preferably H₂SO₄ or CH₃ SO₃ H, in a suitable solvent, such as CH₂ Cl₂, at -40° to+25° C., preferably 0° to +5° C., then warmed to about 15° to 75° C.,preferably 25° to 40° C., for 1 to 18 hours, preferably about 2 to 6hours. The resulting product is treated with a hydride reducing agent,preferably TBAB or NaBH₄, in a suitable solvent, preferably CH₂ Cl₂ oran alcohol solvent, such as isopropanol, at -30° to 50° C., preferablyat 0° to 25° C., for 1/2 to 5 hours, preferably about 1.5 to 2 hours togive a compound of the formula I.

The present invention further comprises a process as described abovewherein the alcohol of Step (a) is prepared according to Process A, asshown in Reaction Scheme A. ##STR31##

In Scheme A, Step A1, L-homophenylalanine (V)is treated with an alkylchloroformate, preferably ClC(O)OCH₃ or ClC(O)OCH₂ CH₃, in the presenceof a strong base, such as NaOH, preferably 1N NaOH, and a base, such asNa₂ CO₃ or K₂ CO₃, at -20° to 20° C., preferably about 0° C., for 30 to90 min then at 0° C. to 50° C., preferably about 30° C., for 30 to 90min. Acidify the mixture to pH 1 to 3 by adding acid, preferably HCl, at-10° to 30° C., preferably about 0° C. to form the carbamate VI, whereinR¹ is as defined above.

In Step A2, the carbamate VI is treated with paraformaldehyde in thepresence of an acid catalyst, preferably pTsOH, and a suitable solvent,such as benzene or toluene, at 40° C. to 120° C., preferably at refluxtemperature, to form the oxazolidinone VII, wherein R¹ is as definedabove.

In Step A3, a Grignard reagent (IX) is prepared from5-bromo-2-chloroanisole and Mg in a suitable solvent, such as THF, at 0°to 60° C., preferably at 40° to 45° C., then reacted with theoxazolidinone (VII) in a suitable solvent, such as THF, at -50° to +10°C., preferably at -20° to -10° C., for 1 to 6 hours, preferably about 5hours, then at 0° to 50° C., preferably about 25° C., for 1 to 6 hours,preferably for about 3 hours, to form the oxazolidine VIII, wherein R¹is as defined above.

Alternatively, in Step A3 the oxazolidinone (VII) is reacted with ametal reagent as described for Step B2 of Reaction Scheme B, below, toform the oxazolidine VIII, wherein R¹ is as defined above.

In Step A4 (i), the oxazolidine VIII is treated with an acid selectedfrom HCl, BF₃.OEt₂, pTSA or HClO₄, preferably 70% HClO₄, in a suitablesolvent, such as THF, at -30° to 20° C., preferably about 0° C., thenwarmed to 100 to 50° C., preferably about 25° C., for 1 to 6 h,preferably about 3 h, to form the ketone X. The ketone X is treated witha hydride reducing agent, preferably LiAlH₄, in a suitable solvent, suchas THF, at -50° to 30° C., preferably about 0° C., then at 40° C. toabout 80° C., preferably at reflux temperature, for 2 to 8 h, preferablyabout 4 h, to form the alcohol II, wherein R is CH₃.

In Step A4 (ii), the oxazolidine VIII is treated with a hydride reducingagent, preferably LiAlH₄, in a suitable solvent, such as THF, at 0° to50° C., preferably about 25° C., to form the alcohol II, wherein R isCH₃.

Alternatively, in Step A4 (i) or Step A4 (ii), where the hydridereducing agent is preferably LiBH₄ or NaBH₄, the treatment is carriedout in a suitable solvent, such as an alcohol, preferably EtOH, at -20°to 20° C., preferably about 0° C., then at 10° to 40° C., preferablyabout 25° C., to give the alcohol II, wherein R is --C(O)OR¹ and R¹ isas defined above.

In an alternative embodiment, the present invention further comprises aprocess as described above wherein the alcohol of Step (a) is preparedaccording to Process B, as shown in Reaction Scheme B. ##STR32##

In Scheme B, Step B 1 (i), the carbamate VI, from Scheme A, Step A1, istreated with N,O-dimethylhydroxylamine, as the free base orhydrochloride, in the presence of BOP, a tertiary amine base, such asEt₃ N or pyridine, and a suitable solvent, such as CH₂ Cl₂, at 0° to 50°C., preferably about 25° C., to form compound XI.

Alternatively, in Step B 1 (ii), the carbamate VI, from Scheme A, Step A1, is treated with SOCl₂ or (COCl)₂ to form an acid chloride. The acidchloride is then treated with N,O-dimethylhydroxylamine, as the freebase or as the hydrochloride, in the presence of a tertiary amine base,such as pyridine, in a suitable solvent, such as CH₂ Cl₂, at 0° to 50°C., preferably about 25° C., to form compound XI.

In Step B2, compound XI is treated with Grignard reagent IX by theprocedure described for Reaction Scheme A, Step A3, to form the ketoneX.

Alternatively, in Step B2, compound XI is treated with a metal reagentof the formula ##STR33## wherein M is selected from ZnL, TiL₃, CeL₂, MnLor CuL, and L is a halide selected from Br, Cl or I. The reaction iscarried out via substantially the same procedure as described for theGrignard reagent in Reaction Scheme A, Step A3, to form the ketone X.

In Step B3, the ketone X is treated with a hydride reducing agent usingthe procedure described for Scheme A, Step A4(i) or A4(ii), to form thealcohol II.

In a second alternative embodiment, the present invention comprises aprocess for preparing compound I according to Process C, as shown inReaction Scheme C. ##STR34##

In Scheme C, Step C1, 5-bromo-2-chloroanisole is treated witht-butyllithium, preferably a solution of t-butyllithium in pentane, in asuitable solvent, such as Et₂ O, at -60° to +10° C., preferably about-15° C., for about 1 h. The ketocarbamate XII is added to the resultingmixture and reacted at 0° to 50° C., preferably about 25° C., for 2-8 h,preferably about 4 h, to form compound XIII.

In Step C2, compound XIII is treated with a trialkylsilane, preferably(CH₃ CH₂)₃ SiH, and CF₃ CO₂ H in a suitable solvent, such as CH₂ Cl₂, at-20° to 50° C., preferably 0° to 25° C., for 1 to 4 h, preferably about1 h, to form the product XIV as a mixture of cis and trans isomers.

In Step C3, the cis/trans mixture of compound XIV is treated with ahydride reducing agent, preferably LiAlH₄, in a suitable solvent, suchas THF, at 30° to 80° C., preferably at reflux temperature, for 30 to 90min, preferably about 1 h, to give compound III is a mixture of cis andtrans isomers.

In Step C₄, the cis/trans mixture of compound III is reacted with acompound of the formula J--CH₂ --Q, wherein J and Q are as definedabove, preferably J is Br and Q is --CH(OCH₃)₂, by the proceduredescribed for Scheme 1, Step (b), to form the compound IV as a mixtureof cis and trans isomers.

In Step C5, the cis/trans mixture of compound IV is treated with analkoxide base, preferably KOC(CH₃)₃ or NaOC(CH₃)₃, in the presence of asuitable solvent mixture, such as DMSO/DMF, at -20° to 50° C.,preferably 0° to 25° C., to give the compound

In Step C6, compound IV is treated according to the procedure describedfor Scheme 1, Step (c), to form compound I.

Starting compounds of the formula XII can be prepared via the processshown in Reaction Scheme D. ##STR35##

In Reaction Scheme D, Step D1, a combination of the chiral amino acid V,a strong base, preferably NaOH, most preferably 1N aqueous NaOH, and abase, preferably Na₂ CO₃, at -20° to +20° C., preferably about 0° C., istreated with ClCO₂ R¹, wherein R¹ is as defined above, preferably R¹ isCH₂ CH₃ or CH₃, then warmed to 0° to 40° C., preferably about 25° C.,for 1 to 5 hours, preferably about 3 hours, then treated with HCl toform the carbamate XV.

In step D2, the carbamate XV is combined with a chlorinating agent, suchas SOCl₂ or oxalyl chloride, preferably SOCl₂, in a suitable solvent,such as CH₂ Cl₂, and heated at 30° to 70° C., preferably at reflux, for1 to 10 hours, preferably about 3 hours, then cooled to about 25° C. Theresulting mixture is treated with a Lewis acid, preferably AlCl₃, in asuitable solvent, such as CH₂ Cl₂, for 1 to 10 hours, preferably about 3hours, to give the ketocarbamate XII.

The starting compound of the formula V is commercially available or canbe prepared via known methods.

The following preparations and examples illustrate the process of thisinvention: ##STR36##

Combine Mg turnings (1.30 g, 54.00 mmol) and 35 mL dry THF. Add asolution of 5-bromo-2-chloroanisole (11.78 g, 53.20 mmol) dissolved in300 mL dry THF over a 10 min. period, maintaining the reactiontemperature at 40°-45° C., and stir for 90 min. The resulting solutionof Grignard reagent is used as is.

Grignard concentration is determined by back titration to aphenolphthalein endpoint. ##STR37##

Combine 5-bromo-2-chloroanisole (24.580 g, 110.981 mmol) and 150 mL Et₂O, cool to -15° C. then add t-butyllithium (130 mL, 221 mmol, 1.7M inpentane) dropwise over 1 h. Stir for 5 min at -15° C., then add theketocarbamate (8.0327 g, 36.641 mmol) portionwise over 5 min and stirfor 4 h at room temperature. Add 100 mL saturated NH₄ Cl and 100 mL CH₂Cl₂, filter, wash the solids with 50 mL CH₂ Cl₂. Add 100 mL saturatedNH₄ Cl to the filtrate and separate the layers. Wash the aqueous layerwith 3×50 mL CH₂ Cl₂, wash the combined organic layers with 1×100 mLbrine. Dry over anhydrous MgSO₄ and concentrate in vacuo to a residue.Flash chromatograph the residue (silica gel, 2:2:1 toluene/hexane/Et₂ O)to give the product, mp: softens 155°-157° C., melts 167°-168° C. ¹ HNMR (CDCl₃)δ: 7.05-7.35 (m, 6H); 6.40 (d, 1H, J=9.4 Hz); 4.40 (d, 1H,J=15 Hz); 4.32 (br. s, 2H); 4.20 (m, 1H); 3.82 (s, 3H); 3.62 (s, 3H);2.90-3.20 (m, 2H); 1.60-1.90 (m, 2H). ##STR38##

Combine the product of Step (a) (1.137 g, 3.142 mmol) and 10 mL CH₂ Cl₂,cool to 0° C., then add triethylsilane (1.30 mL, 8.14 mmol) and stir for15 min at room temperature. Cool to 0° C., add TFA (6.10 mL, 79.2 mmol)and stir for 1 h at room temperature. Add 10 mL saturated NaHCO₃ and 25mL CH₂ Cl₂, separate the layers, wash the aqueous layer with 1×25 mL CH₂Cl₂. Combine the organic layers and wash with 1×20 mL brine, then dryover anhydrous MgSO₄ and concentrate in vacuo to yield the product as amixture of cis and trans isomers. trans isomer: ¹ H NMR (CDCl₃) δ:7.05-7.30 (m, 7H); 6.85 (d, 1H, J=7.5 Hz); 6.71 (s, 1H); 6.55 (dd, 1H,J= 1.5, 7.5 Hz); 4.80 (br. s, 1H); 4.08 (br. s, 2H); 3.82 (s, 3H); 3.61(s, 3H); 2.85-3.07 (m, 2H); 2.05-2.15 (m, 1H); 1.70-1.90 (m, 1H). cisisomer: ¹ H NMR (CDCl₃) δ: 6.47-7.25 (m, 7H); 4.20-4.50 (m, 3H); 3.80(s, 3H); 3.67 (s, 3H); 3.02 (m, 2H); 1.68-1.90 (m, 2H). ##STR39##

Dissolve the cis/trans product of Step (b) (364.4 mg, 0.881 mmol) in 5mL THF, add LiAlH₄ (2.80 mL, 2.80 mmol, 1M in Et₂ O) and heat at refluxfor 1 h. Cool to room temperature then add 10 mL saturated NaHCO₃ and 25mL CH₂ Cl₂. Separate the layers and wash the aqueous layer with 2×10 mLCH₂ Cl₂. Combine the organic layers, wash with 1×10 mL saturated salt,dry over anhydrous MgSO₄ and concentrate in vacuo to yield the productas a mixture of cis and trans isomers. trans isomer: ¹ H NMR (CDCl₃) δ:6.17-7.32 (m, 7H); 3.90 (d, 1H, J=7.5 Hz); 3.85 (s, 3H); 2.80-3.0 (m,3H); 2.40 (s, 3H); 2.20-2.30 (m, 1H); 1.30-1.80 (m, 2H). cis isomer:.sup. 1 H NMR (CDCl₃) δ: 6.52-7.35 (m, 7H); 4.35 (d, 1H, J=5.6 Hz); 3.81(d, 1H, J=7.5 Hz); 2.85-3.10 (m, 3H); 2.50 (s, 3H); 1.30-1.99 (m, 3H).##STR40##

Combine the cis/trans product of Step (c) (2.01 g, 6.66 mmol), K₂ CO₃(9.282 g, 66.7 mmol, milled), bromoacetaldehyde dimethyl acetal (4.00mL, 33.8 mmol) and 20 mL DMF in a Teflon® acid digestion bomb, seal andheat at about 110° C. for 3 days. Cool to room temperature, add 25 mLsaturated NaHCO₃, 25 mL water and 50 mL t-BuOMe, and separate thelayers. Wash the aqueous layer with 2×50 mL t-BuOMe, then wash thecombined organic layers with 3×25 mL water and 1×10 mL brine. Dry overMgSO₄ and concentrate/n vacuo to a residue. Flash chromatograph theresidue (silica gel, 30-50% EtOAc/hexanes) to yield the product as amixture of trans and cis isomers (1:3.6 ratio). trans isomer: ¹ H NMR(CDCl₃) δ: 6.65-7.30 (m, 7H); 4.12 (t, 1H, J=5.6 Hz); 4.09 (d, 1H,J=11.3 Hz); 3.82 (s, 3H); 3.21 (s, 3H); 3.12 (s, 3H); 2.95 (m, 3H); 2.60(dd, 2H, J=5.6, 11.3 Hz); 2.31 (s, 3H); 2.08 (m, 1H); 1.70-1.80 (m, 1H).cis isomer: ¹ H NMR (CDCl₃) δ: 6.65-7.35 (m, 7H); 4.51 (t, 1H, J=5.6Hz); 4.09 (d, 1H, J=11.3 Hz); 3.82 (s, 3H); 3.40 (2s, 6H); 2.40-2.90 (m,3H); 2.32 (s, 3H); 2.25 (m, 1H); 2.08 (m, 1H); 1.51-1.81 (m, 1H).##STR41##

Dissolve the cis/trans product of Step (d) (280.9 mg, 0.720 mmol) in 2mL of freshly degassed DMSO. Add 1 mL freshly degassed DMF, cool to 0°C., add KOC(CH₃)₃ (172.8 mg, 1.540 mmol) and stir for 1 h at roomtemperature. Add 15 mL saturated NaHCO₃, 20 mL t-BuOMe and 5 mL water.Separate the layers and wash the aqueous layer with 3×15 mL t-BuOMe.Combine the organic layers, wash with 4×5 mL water, dry over anhydrousMgSO₄ and concentrate in vacuo to yield a 51:1 mixture of the trans andcis isomers. Flash chromatograph (silica gel, 30-50% EtOAc/hexanes) togive the trans product. ¹ H NMR (CDCl₃) δ: 6.65-7.30 (m, 7H); 4.12 (t,1H, J=5.6 Hz); 4.09 (d, 1H, J=11.3 Hz); 3.82 (s, 3H); 3.21 (s, 3H); 3.12(s, 3H); 2.95 (m, 3H); 2.6 (dd, 2H, J=5.6, 11.3 Hz); 2.31 (s, 3H); 2.08(m, 1H); 1.70-1.80 (m, 1H). ##STR42##

Combine methanesulfonic acid (7.40 g, 77.003 mmol) and 15 mL CH₂ Cl₂ andcool to 0° to 5° C. Dissolve the product of Step (e) (2.34 g, 6.001mmol) in 15 mL CH₂ Cl₂ and add the resulting solution to the acidsolution over a 5 min period. Heat the mixture at 40° C. for 2 h, thenconcentrate (50° C./20 Torr) to a residue. Dissolve the residue in 10 mLCH₂ Cl₂, cool to 10° to 15° C., and add a solution of NaBH₄ (0.280 g,7.402 mmol) in 15 mL i-PrOH over a 10 min period. Stir for 2 h, then adda solution of Na₂ CO₃ (6.70 g, 63.208 mmol) in 34 mL water to adjust topH 7. Extract the aqueous layer with 2×10 mL CH₂ Cl₂, wash the combinedorganic layers with 2×10 mL water, then dry over anhydrous MgSO₄ andconcentrate in vacuo to yield the (-)-enantiomer of the title compound.Purify by flash chromatograph (silica gel, 2.5-10% MeOH/CH₂ Cl₂). ¹ HNMR (CDCl₃) δ: 6.95-7.19 (m, 5H); 5.88 (s, 1H); 4.78 (d, 1H, J=7.5 Hz);3.5-3.62 (m, 1H); 3.49 (s, 3H); 3.2 (dd, 1H, J=3.75, 11.3 Hz); 2.65-2.86(m, 4H); 2.51 (s, 3H); 2.41 (dd, 1H, J=5.6, 11.3 Hz); 1.98-2.18 (m, 1H);1.6-1.8 (dq, 1H, J=5.6, 11.3 Hz).

Using substantially the same procedure, the title compound can beprepared from the product of Step (e) using H₂ SO₄ in place ofmethanesulfonic acid.

EXAMPLE 2 ##STR43##

Combine L-homophenylalanine (25.0 g, 0.139 mole) and 1.0N NaOH (280 mL,0.280 mole), add 1.5 eq of Na₂ CO₃ (22.2 g, 0.209 mole) and cool to 0 °C. Add ethyl chloroformate (30.4 g, 0.280 mole) dropwise, stir for 1.0 hthen warm to 30 ° C. and stir for an additional hour. Cool to 0 ° C. andacidify to pH=2 with 10% aq HCl. Add 200 mL of CH₂ Cl₂, separate thelayers and wash the aqueous layer with 2×200 mL of CH₂ Cl₂. Combine theorganic layers, wash with brine, then dry over MgSO₄. Concentrate invacuo to give the carbamate product. ¹ H NMR (CDCl₃) S: 7.4-7.2 (5H, m);5.22 (1H, d, J=7.1Hz); 5.5-5.4 (1H, m); 4.19 (2H, q, J=6.9 Hz), 2.77(2H, t, J-7.9 Hz); 2.4-2.2 (1H, m); 2.1-2.0 (1H, m); 1.30 (3H, t, J=7.0Hz). ##STR44##

Combine the carbamate of Step (a) (20.0 g, 79.6 mmol), paraformaldehyde(4.80 g, 160 mmol), p-TSA (0.908 g, 4.77 mmol) and 800 mL of benzene.Heat the mixture at reflux using a Dean-Stark trap to remove water untilTLC (silica gel, 30% EtOAc/hexane) shows no unreacted starting material.Dilute the reaction mixture with 100 mL of EtOAc, then wash with 10 mLof 0.3M Na₂ CO₃ and 2×25 mL of brine. Dry over MgSO₄ and evaporate togive the oxazolidinone product. ¹ H NMR (CDCl₃) δ: 7.4-7.2 (5H, m); 5.55(1H, s); 5.22 (1H, d, J=3 Hz); 4.4-4.1 (3H, m); 2.9-2.7 (2H, m); 2.4-2.2(2H, m); 1.32 (3H, t, J=5 Hz). ##STR45##

Stir a solution of oxazolidinone of Step (b) (5.00 g, 19.1 mmol) in 19.1mL of dry THF at -15° C. under nitrogen and add 1.12 eq of the Grignardreagent from Preparation 1 via syringe pump at a rate of 0.57 mL/min.Allow the mixture to warm to room temperature and stir for 3 h. Cool to0 ° C., then quench with 20 mL of 5% HCl. Add 250 mL EtOAc, separate thelayers and wash the aqueous layer with 50 mL of EtOAc. Combine theorganic layers and wash with brine, then dry over MgSO₄ and concentratein vacuo to a residue. Purify the residue by flash chromatography(silica gel, 97:3 to 92:8 EtOAc/CH₂ Cl₂) to give oxazolidine product asa mixture of diastereomers. ¹ H NMR (CDCl₃) δ7.5-7.0 (8H, m); 5.8-5.7(m); 5.5-5.3 (m); 5.1-4.8 (m); 4.3-4.1 (m); 3.88 (3H, s); 3.9-3.3 (m);2.9-2.6 (m), 2.3-2.1 (m); 1.68 (3H, s); 1.4-1.1 (m). ##STR46##

Combine the oxazolidine product of Step (c) (1.86 g, 4.6 mmol), water(3.9 g, 21.5 mmol) and 18 mL of THF, and cool to 0 ° C. Add 70% HClO₄(6.12 g, 15.4 mmol) dropwise over 10 min, then warm to room temperatureand stir for 3 h. Quench the reaction with 30 mL of aq NaHCO₃ andextract with EtOAc (3'30 mL). Combine the organic layers and wash withbrine. Dry over MgSO₄ and concentrate in vacuo to a residue. Purify theresidue by flash chromatography (99:1 to 97:3 EtOAc/CH₂ Cl₂) to give theketone product. ¹ H NMR (CDCl₃) δ: 7.5-7.2 (8H, m); 5.66 (1H, d, J=8.1Hz); 5.35 (1H, dt, J=3.6, 8.3 Hz); 4.21 (2H, q, J=7.1 Hz); 3.91 (3H, s);2.8-2.6 (2H, m); 2.3-2.1 (1H, m); 2.0-1.8 (1H, m); 1.32 (3H, t, J=7.1Hz). ##STR47##

Add LiAlH₄ (1M in ether, 4.5 mL, 4.5 mmol) to a mixture of the ketone ofStep (d) (0.34 g, 0.90 mmol) and 9 mL of THF at 0° C. Heat the mixtureat gentle reflux for 4 h. Cool to room temperature and quench withaqueous saturated NH₄ Cl. Extract the crude product with Et₂ O, wash theorganic layer with brine, dry over MgSO₄ and concentrate in vacuo togive the alcohol product. ¹ H NMR (CDCl₃) δ: 7.4-6.8 (8H, m); 4.95 (1H,d, J=3 Hz), 4.42 (1H, d, J=5Hz); 3.93 (3H, s); 2.7-2.4 (3H, m); 2.58(3H, s); 2.07 (1H, s), 1.8-1.5 (2H, m). ##STR48##

Add CF₃ SO₃ H (131 mg, 0.87 mmol) to a mixture of the alcohol of Step(e) (0.014 g, 0.044 mmol) and 0.1 mL CH₂ Cl₂ at 0° C. Warm to roomtemperature and stir overnight. Dilute the mixture with Et₂₀ and basifywith saturated NaHCO₃. Separate the organic layer, wash with brine, dryover MgSO₄ and concentrate in vacuo to give the title compound. ¹ H NMR(CDCl₃) δ: 7.4-7.1 (4H, m); 6.8-6.7 (3H, m); 3.96 (1H, d, J=6 Hz); 3.90(3H, s); 3.03 (2H, t, J=5 Hz); 2.92 (1H, dt, J=2 6 Hz); 2.48 (3H, s);2.3-2.2 (1H, m); 1.8-1.6 (1H, m).

EXAMPLE 3 ##STR49##

Add NaBH₄ (0.055 g, 1.3 mmol) to a solution of the ketone of Example 2,Step (d) (0.50 g, 1.3 mmol) in 13 mL of EtOH at 0° C., then allow themixture to warm to room temperature. Monitor the reaction by TLC (silicagel, 7:3 hexane/EtOAc). When the reaction is complete, quench with 8 mLof saturated NaHCO₃, filter and wash the solids with Et₂ O. Concentratethe filtrate in vacuo to a residue, dissolve the residue in Et₂ O, washsequentially with saturated NaHCO₃, and brine, then dry over MgSO₄.Concentrate in vacuo to give the alcohol product. ¹ H NMR (CDCl₃)δ:5:7.4-6.8 (7H, m); 4.9-4.7 (2H, m); 4.22 (2H, q, J=9 Hz); 3.92 (3H, s);4-3.9 (1H, m); 3.05 (1H, s); 2.8-2.7 (1H, m); 1.7-1.5 (1H, s); 1.9-1.5(2H, m); 2.32 (3H, t, J=9 Hz). ##STR50##

Add CH₃ SO₃ H (0.41 g, 0.43 mmol) to a solution of the alcohol productof Step (a) (0.160 g, 0.423 mmol) in 2.0 mL CH₂ Cl₂ at 0° C., then warmto room temperature and stir overnight. Dilute the reaction mixture with20 mL of Et₂ O, basify with 5.0 mL of saturated NaHCO₃ and separate theorganic layer. Wash the aqueous layer with 2×20 mL of Et₂ O, combine theorganic layers, wash with 5.0 mL of brine, and dry over MgSO₄.Concentrate in vacuo to residue and purify the residue by preparativeTLC (silica gel, 30:70 EtOAc/hexane) to give the product. ¹ H NMR(CDCl₃)δ: 7.4-7.1 (4H, m); 6.92 (1H, d, J=7.4 Hz); 6.79 (1H, s); 6.62(1H, dd, J=1.8, 8.1 Hz); 4.87 (1H, s); 4.2-4.1 (4H, m); 3.90 (3H, s);3.1-2.9 (2H, m); 2.2-2.1 (1H, m); 1.9-1.8 (1H, m); 1.26 (3H, t, J=7.0Hz). ##STR51##

Add 1M solution of LiAlH₄ in Et₂₀ (1.34 mL, 1.34 mmol) to a solution ofthe Product of Step (b) (0.120 g, 0.334 mmol) in 3.3 mL of dry THF. Heatthe mixture at reflux and monitor the reaction by TLC. When the reactionis complete, cool the mixture to room temperature, and quench withsaturated NH₄ Cl. Extract with Et₂₀ (3×20 mL), combine the organiclayers, wash with brine and dry over MgSO₄. Concentrate in vacuo andpurify the resulting residue by preparative TLC (silica gel, 100:10:1CH₂ Cl₂ /MeOH/NH₄ OH) to give the title compound.

EXAMPLE 4 ##STR52##

React L-homophenylalanine with methyl chloroformate according to theprocedure described for Example 2, Step (a) to form the carbamateproduct. ¹ H NMR (CDCl₃)δ: 7.4-7.2 (5H, m); 5.4-5.3 (1H, m); 4.5 (1H,m); 3.77 (3H, s); 2.78 (2H, t, J=8.0 Hz); 2.3 (1H, m); 2.1 (1H, m).##STR53##

Add Et₃ N (1.26 g, 12.5 mmol) to a solution of the product of Step (a)(2.97 g, 12.5 mmol) in 60 mL CH₂ Cl₂. Add a solution of BOP (5.53 g,12.5 mmol) in 30 mL CH₂ Cl₂ and stir for 20 min at room temperature. AddN,O-dimethylhydroxylamine hydrochloride (1.34 g, 13.7 mmol) and Et₃ N(1.26 g, 12.5 mmol), and stir the mixture while monitoring by TLC(silica gel, 95:5 CH₂ Cl₂ /MeOH), adding Et₃ N (1.26 g, 12.5 mmol) toensure completion of the reaction. Add 300 mL of CH₂ Cl₂ and washsequentially with 2×125 mL of 10% HCl, saturated aq NaHCO₃ and brine.Dry the organic layer over MgSO₄ and concentrate in vacuo to a residue.Purify the residue by flash chromatography (silica gel, 98.5:1.5 CH₂ Cl₂/MeOH) to give the product. ¹ H NMR (CDCl₃)δ: 7.3-7.2 (5H, m); 5.53 (1H,d, J=9.0 Hz); 4.8-4.7 (1H, m); 3.75 (3H, s); 3.67 (3H, s); 3.22 (3H, s);2.9-2.6 (2H, m); 2.2-1.9 (2H, m). ##STR54##

Add 2.5 eq of the Grignard reagent from Preparation 1, dropwise, to asolution of the product of Step (b) (0.477 g, 1.70 mmol) in 6 mL of dryTHF at 0° C. Stir the mixture and warm to room temperature, whilemonitoring by TLC (silica gel, 95:5 hexane/EtOAc), until the reaction iscomplete. Quench the reaction with 10 mL of EtOH and 10 mL of 5% HCl,and extract with a solution of 1:1 CH₂ Cl_(2/) Et₂ O. Dry the organiclayer over MgSO₄, concentrate in vacuo and purify the resulting residueby flash chromatography (silica gel, 95:5→85:15, EtOAc/hexane) to givethe ketone product. ¹ H NMR (CDCl₃)δ: 7.4-7.2 (8H, m); 5.72 (1H, d, J=8Hz); 5.33 (1H, dt, J=4, 8 Hz); 3.89 (3H, s); 2.8-2.6 (2H, m); 2.3-2.1(1H, m); 2.0-1.8 (1H, m). ##STR55##

The product of Step (c) is reacted with NaBH₄ according to the proceduredescribed for Example 3, Step (a), to give the alcohol product. ¹ H NMR(CDCl₃)δ: 7.4-7.0 (5H, m); 6.9-6.8 (2H, m); 4.9-4.8 (2H, m); 4.0-3.9(1H, m); 3.90 (3H, s); 3.75 (3H, s); 2.95 (1H, s); 2.8-2.5 (2H, m);1.9-1.5 (2H, m). ##STR56##

The product of Step (d) is reacted with CH₃ SO₃ H according to theprocedure of Example 3, Step (b), to give the title compound. ¹ H NMR(CDCl₃)δ: 7.3-7.1 (4H, m); 6.93 (1H, d, J=7.8 Hz); 6.8 (1H, s); 6.64(1H, dd, J=1.8, 9.8 Hz); 4.92 (1H, s); 3.91 (3H, s); 3.70 (3H, s);3.2-2.9 (2H, m); 2.2-2.1 (1H, m); 2.0-1.8 (1H, m).

We claim:
 1. A process for preparing a compound of the formula ##STR57##comprising the steps: (C1) reacting a ketocarbamate of the formula##STR58## wherein R¹ C₁ -C₆ alkyl or --CH₂ C₆ H₅ with the lithiumreagent prepared from 5-bromo-2-chloroanisole and t-butyllithium, toform a compound of the formula ##STR59## wherein R¹ is as defined above;(C2) reacting the product of step (C1) with a trialkylsilane and CF₃ CO₂H to form a compound of the formula ##STR60## wherein R¹ is as definedabove, as a mixture of cis and trans isomers;(C3) reducing the productof step (C2) by treating with a hydride reducing agent to form acompound of the formula ##STR61## as a mixture of cis and trans isomers;(C4) reacting the product of Step (C3) with a compound of the formulaJ--CH₂ --Q, wherein J is a leaving group, and Q is a group of theformula ##STR62## wherein R² is C₁ -C₆ alkyl, to form a compound of theformula ##STR63## as a mixture of cis and trans isomers; (C5) treatingthe product of step (C4) with an alkoxide base to form a compound of theformula ##STR64## (C6) cyclizing the product of step (C5) to form thecompound of formula I.
 2. A process according to claim 1 wherein: R¹ isCH₃ -- or CH₃ CH₂ --; the trialkylsilane of Step (C2) is triethylsilane;the hydride reducing agent of Step (C3) is LiAlH₄ ; J is Br; thealkoxide base of Step (C5) is KOC(CH₃)₃ or NaOC(CH₃)₃ ; and in Step (C6)cyclizing comprises treating the product of Step (C5) with a strongacid, then with a hydride reducing agent.
 3. A process according toclaim 2 wherein: the strong acid of Step (C6) is H₂ SO₄ or CH₃ SO₃ H;and the hydride reducing agent of Step (C6) is TBAB or NaBH₄.